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Synthesis runs counter to directional folding of a nascent protein domain.

Xiuqi ChenNandakumar RajasekaranKaixian LiuChristian M Kaiser
Published in: Nature communications (2020)
Folding of individual domains in large proteins during translation helps to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observed in vitro for the majority of proteins relate to co-translational folding remains unclear. Combining in vivo and single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway initiating from the C-terminus. Folding and synthesis thus proceed in opposite directions. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.
Keyphrases
  • single molecule
  • molecular dynamics simulations
  • atomic force microscopy
  • living cells
  • amino acid
  • small molecule
  • binding protein
  • endoplasmic reticulum stress